Process for preparating lower alkyl 2-pyridinium aldoxime salts



United States Patent 3,385,860 PROCESS FOR PREPARING LOWER ALKYLZ-PYRIDINlUM ALDOXIME SALTS Richard Bennett Margerison, Florham Park,and John Archibald Nelson, Morris Plains, N.J., assignors to CibaCorporation, New York, N.Y., a corporation of Delaware No Drawing.Continuation-impart of application Ser. No. 462,388, June 8, 1965. Thisapplication July 19, 1966, Ser. No. 566,222

16 Claims. (Cl. 260-496) ABSTRACT OF THE DISCLOSURE The inventioninvolves a novel procedure for preparing lower alkylZ-pyridinium-aldoxime salts, more particularly the Z-pyrid-ine-aldoximemethohalides, such as the methochloride. The process involves mixing alower alkyl 2-picolinium salt with an alkyl nitrite, adding a basematerial to the reaction mixture and finally neutralizing with an acidto obtain the desired product. The products produced by this procedureare anti-cholinesterase inhibitors.

This is a continuation-in-part of application Ser. No. 462,388, filedJune 8, 1965, now abandoned, which is in turn a continuation-in-p-art ofapplication Ser. No. 324,- 226, filed Nov. 18, 1963, and now abandoned.

The present invention concerns a novel procedure for the preparation oflower alkyl Z-pyridinium-aldoxime salts, more particularly the2-pyridine-aldoxime methohalides, especially the Z-pyridine-aldoximemethochloride (2-PAM chloride), which compounds are potentanticholinesterase inhibitors.

Procedures available for the preparation of these compounds eithercomprise the formation of picolinaldehyde, which is then converted intoits oxime and the latter is quaternized with a reactive ester of a loweralkanol, or the formation of a lower alkyl 2-picolinium salt, itsconversion into the corresponding base or anhydrob-ase, which is reactedwith a nitrosating agent, such as a nitrosyl halide or an alkyl nitrite(US. Patent No. 3,155,674).

The former method, requiring picolinaldehyde, represents a cumbersomeprocedure involving many steps for isolation and purification ofintermediates. The latter method, requiring the liberation of thetertiary bases or anhydrobases respectively, does not providesatisfactory yields and final products, since said bases are highlyunstable compounds which cannot be handled without risk of considerableloss on a large scale basis.

We have now found that lower alkyl 2-pyridinium aldoxime salts can beprepared satisfactorily, especially in higher yields and of higherpurity than according to the procedure illustrated in said US. patent,by

(a) reacting a lower alkyl 2-picolinium salt with an aliphatic nitrite,advantageously in approximately a molar ratio,

(b) adding to the reaction mixture a base, advantageously an equivalentamount of an alkali metal hydroxide at a temperature not exceeding roomtemperature and,

(c) neutralizing the reaction mixture with an acid, advantageously ahydrohalic acid.

The aliphatic nitrite used in the present process is, more particularly,an alkyl nitrite, preferably a lower alkyl nitrite and advantageously aliquid lower alkyl nitrite, especially one containing 3 to 5 carbonatoms, such as isopropyl, n-butyl or preferably isopentyl (isoamyl)nitrite. It may also be a gaseous alkyl nitrite, such as ethyl nitrite,or a solid alkyl nitrite.

As mentioned above, the base used in the present proc- "ice ess ispreferably an alkali metal hydroxide, such as sodium or potassiumhydroxide. Of course, one may obviously use a material which providesthe alkali metal hydroxide, in situ, under the conditions of thereaction, such as an alkoxide of the alkali metal hydroxide. Inaddition, the base may be a quaternary ammonium hydroxide, such as atetra-lower alkyl-quaternary ammonium hydroxide, (e.g., tetra-methylammonium hydroxide, tetra-ethyl ammonium hydroxide, etc.), abenzyl-tri-lower alkyl ammonium hydroxide (e.g., benzyl-tri-methylammonium hydroxide, benzyl-tri-ethyl ammonium hydroxide, etc.), or asimilar organic base. The acid used is preferably a hydrohalic acid,(e.g., hydrochloric, hydrobromic or hydrohalic acid), e.g., hydrochloricor hydrobromic or hydrohalic acid as well as sulfuric or sulfonic acidor a strong organic acid, particularly a sulfonic acid such as a loweralkane or benzene sulfonic acid, e.g., methane, ethane, benzene, orp-toluene sulfonic acid or a monolower alkyl sulfate, e.g., methyl orethyl sulfate. The acid may also be a lower alkane carboxylic acid,e.g., acetic acid, propionic acid, etc. or a halogenated-lower alkanecarboxylic acid, e.g., trichloro-acetic acid, tribromo-acetic acid,tetrachloro-acetic acid and the like.

The process of this invention is carried out according to standardmethods, advantageously in the presence of diluents, preferably such asare inert to the reagents and are solvents thereof, for example ofWater, of alcohols, such as lower alkanols, e.g., methanol, ethanol,isoprop'anol, n-butanol or isopentanol, of ketones, such as loweralkanones, e.g., acetone, or of mixtures thereof with or without water,of catalysts and/or inert atmospheres advantageously at lowtemperatures, for example in the range between 0 and room temperature,preferably between -10 and +10 C. for the nitrosation, at atmospheric orsuperatmospheric pressure.

The invention also comprises the modification of the process, whereinthe aliphatic nitrite and the base are added simultaneously or wherein acompound obtainable as an intermediate at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions.

Mainly those starting materials should be used that lead to theformation of those compounds indicated above as being the preferredembodiments of the invention.

The starting materials are known or, if new, may be prepared accordingto methods known per se.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. The temperatures aregiven in degrees centigrade.

EXAMPLE 1 To a stirred solution of 18.81 g. picolinium methobromide in25 ml. methanol and 15 ml. water, 17.56 g. isoamyl nitrite are added andhereupon a solution of 8.0 g. sodium hydroxide in 12 ml. water and 10ml. methanol Within a half hour period while keeping the temperature at5l0 and allowing the reaction mixture to stand for 2 days at 5. Hereupon10% aqueous hydrochloric acid is added to adjust the pH of about 4 andthe mixture is concentrated in vacuo at 0-20.

The solid residue (A) is leached twice with two 40 ml. portions ofethanol and upon concentrating the solution and cooling it, there areobtained 1.73 g. of crude product (B). Three extractions of thesolid Awith 30 ml. methanol each yield after concentrating and cooling another14.34 g. of crude product (C). The combined products B and C arerecrystallized from methanol with the 3 aid of charcoal to yield 12.29g. of 95% pure 2-pyridine aldoxime metho'bromide of the formula To astirred solution of 14.37 g. picolinium methochloride in 25 ml. methanoland 15 ml. water, 15.5 g. n-butyl nitrite are added and hereupon asolution of 8.0 g. sodium hydroxide in 12 ml. water and 10 ml. methanolduring about 15 minutes at 510. After keeping the reaction mixture at 5overnight, 10% aqueous hydrochloric acid is added to reach a pH of about4 and the mixture is evaporated to dryness under reduced pressure at 20.

The solid residue is washed twice with 40 ml. portions each ofisopropanol and ethanol followed by three 40 ml. portions of warmmethanol. Concentrating and cooling the methanol solution yields a firstcrop of 5.63 g. of 95% pure product. Further concentrating the motherliquor followed by the addition of acetone and diethyleneglycol dimethylether gives a second crop of 7.32 g. of 90-95% pure 'product and asecond treatment a third crop of 1.36 g. of 60-70% pure product. Thecombined crops are recrystallized from methanol followed by the additionof acetone and yield a (l) crop of 2.30 g. of 95% pure, a

(2) crop of 2.62 g. of 95% pure and (3) crop of 7.24 g. of 90-95% pure2-pyridine aldoxime methochloride of the formula l CH2 EXAMPLE 3Following the procedure shown in Example 2 but using instead of n-butylnitrite 17.56 g. isoamyl nitrite, there are obtained after the tworecrystallizations from methanol-acetone 3 crops of totally 10.63 g.2-pyridine aldoxime methochloride having a purity of about 95%.

EXAMPLE 4 A 5 liter flask is charged with 866.1 g. picolinemethochloride solution containing 3 moles thereof (prepared as describedbelow). To this stirred solution 666 ml. methanol are added and aftercooling to 368 g. isoamyl nitrile are added and cooling is continueduntil the temperature of 0 is reached. Hcreupon a solution of 377 g. 50%aqueous sodium hydroxide in 120 ml. water and 300 ml. methanol is addedat such a rate that the reaction temperature does not exceed 10. Themixture is stirred at 0 for 4 hours and stored in the refrigeratorovernight. The following morning the batch is neutralized to a pH ofabout 4 with about 320 ml. concentrated hydrochloric acid while keepingthe temperature below 10. The mixture is concentrated in vacuo to about1 liter while maintaining the temperature below 35. The semicrystallineresidue is diluted with 1 liter isoamyl alcohol and vacuum distillationis continued until about 1 liter remains. This is repeated once more inorder to remove Water azeotropically. The residue is cooled to 10overnight, filtered and sucked dry on the tunnel. The filter cake iswashed first with two 250 ml. portions of isopropanol and then with two250 ml. portions acetone and is dried in vacuo at 50. The soobtaincd 600g. brown cake is refluxed with 2 liter 0.5 N methanolic hydrochloricacid and 30 g. charcoal for minutes, then filtered and the residuewashed twice with 100 ml. portions of 0.5 N rnethanolic hydrochloricacid.

The filtrate is cooled to 0 overnight and the precipitated pyridinealdoxime methochloride filtered off and washed twice with 200 ml.portions of acetone and dried in vacuo at 50; yield 256 g. The filtrateand washings are concentrated to about 300 ml. in vacuo and the residuecooled to 0 yielding a second crop of 21.1 g. of the same material.

Both crops are combined and dissolved in 1650 ml. boiling 0.5 Nmethanolic hydrochloric acid and 27.7 g. charcoal are added. The mixtureis stirred and refluxed for 15 minutes, then filtered and the residuewashed with 277 ml. 0.5 N methanolic hydrochloric acid. The filtrate andwash is concentrated at reduced pressure to 1500 ml. and cooled to 0overnight. The precipitate is filtered off and Washed once with 250 ml.isopropanol and once with 250 ml. acetone; yield 244 g. first crop and23.4 g. second crop (from 300 ml. mother liquors).

The first crop (244 g.) is dissolved in 195 ml. deionized water at 30and the solution stirred for 15 minutes with 12.3 g. charcoal andfiltered. The residue is washed twice with each 12 ml. water and thefiltrate diluted with 540 ml. isopropanol. It is cooled to 10 overnight,the precipitate formed filtered olf, washed once with 250 ml.isopropanol and once with 250 ml. acetone and dried in vacuo at 50 yield202 g. pyridine aldoxime methochloride melting at 225 withdecomposition. This product meets the specifications for preparinginjectable solutions. A second crop of 35.8 g. is obtained by strippingthe mother liquors to near dryness and adding ml. isopropanol.

Both second crops (59.2 g.) require two crystallizations, one frommethanolic hydrochloric acid and one from isopropanol water to yield theabove pure product in about the same proportion.

The starting material can be obtained as follows:

A 1 gallon Sutherland reactor is charged with 931.3 g. 2-picoline and150 ml. water. It is sealed, flushed first with nitrogen and then withmethyl chloride. The mixture is heated to 100-103 with stirring and thenthe internal pressure is adjusted to 20 p.s.i.g. with methyl chloride.The reaction is allowed to progress until no further uptake of methylchloride can be noticed. The reactor is purged of excess methylchloride, the mixture diluted with 1 liter water and blown from thereactor with nitrogen. The reactor is washed with 350 ml. water and thewash is added to main batch. This aqueous solution of 2-picoliniummethochloride is used in the above reaction. When titrated with standardmercuric nitrate using diphenyl carbazone as indicator it contains theproduct in an amount correspondin to 94% of theory calculated from theionizable chloride content.

A 5 liter flask with efficient stirrer is charged with 440.8 g. isoamylalcohol, cooled to 10, and 260 g. technical sulfuric acid in 1100 ml.water are added in such a rate that the temperature maintains below 15.The resulting emulsion is cooled to 0 and a solution of 380 g. sodiumnitrite in 2.5 liter water is added at a temperature between 1 and 1. Itis stirred at 0 for one hour and then the organic layer is allowed toseparate. It is collected, dried over 50 g. magnesium sulfate, filteredand stored at 0-5"; it represents the isoamyl nitrite used in the abovereaction.

EXAMPLE 5 A two liter round-bottomed flask is charged with 304 ml. of al-molar aqueous solution of 2-picoline methochloride and 322 m1.n-butanol whereupon 108.3 g. nbutyl nitrite are added. The solution isstirred and cooled in an ice salt bath to 0 and a solution of 1253 g.50% aqueous sodium hydroxide in 40 ml. water is added while maintainingthe temperature between -1 and 1. The batch is stirred for 3 hours andstored at 10 overnight. The following morning it is acidified to pH 4 bythe addition of about ml. concentrated hydrochloric acid, whilemaintaining the temperature near 0. The reaction mixture is concentratedto about half the original volume at aspirator pressure, the residue isdiluted with 250 ml. n-butanol and again concentrated to half thevolume. This is repeated twice more and the final concentration iscarried to the point Where no additional water distills over. Thesuspension obtained is cooled to while standing overnight. The crude2-pyridine aldoxime methochloride and sodium chloride is filtered offand dried in vacuo at 60 C. to yield 244.5 g.

The salt cake obtained is stirred with 660 ml. methanol and the slurryis heated to reflux. The suspension is treated with 10 g. charcoal andclarified by filtration. The filter cake is washed with 100 ml. of hotmethanol and the filtrate and wash is concentrated to 290 ml. atatmospheric pressure. The solution is cooled to 10 C. and theprecipitate is filtered 011 and washed with two ml. portions of methanolof -10 and dried in vacuo at Yield 128.6 g. of a first crop melting at219 (dec.) and 13.2 g. of a second crop melting at 214 (dec.) byconcentrating the mother liquors to ml. Both crops are dissolved in 780ml. boiling methanol, treated with 9.75 g. charcoal and clarified byfiltration. The filter cake is Washed with ml. hot methanol and thetotal filtrate is concentrated to 390 ml. at atmospheric pressure. Theslurry is cooled to 10 and the precipitate collected on a funnel. Thefilter cake is washed with two 50 ml. portions of methanol at 10 C. anddried in vacuo at 60 C. Yield: Crop 1=123.5 g., Crop 11:14.35 g.

Crop I is dissolved in 98 ml. water at 40 C., treated with 6.2 g.charcoal and clarified by filtration. The filter cake is washed with two6 ml. portions of water and the filtrate and washes are diluted with 440ml. isopropanol. The slurry is cooled to 10 and the pure Z-pyridinealdoxime methochloride is collected on a funnel, washed with two 50 ml.portions of isopropanol and dried in vacuo at 60. Yield 102 g. of thefirst crop melting at 224 (dec.), and Crop I1 l7.45 g.

The combined second crops from the methanol and aqueous isoprop-anolpurification steps are purified twice in the same manner and yield anadditional 10% of pure 2-pyridine aldoxime methochloride melting at 224(dec.).

What is claimed is:

1. The process for the preparation of lower alkyl 2- pyridinium-aldoximesalts which comprises (a) mixing a lower alkyl 2-picoliniurn salt Withan alkyl nitrite,

(b) adding to the reaction mixture a base selected from the grouconsisting of an alkali metal hydroxide, a tetra-lower alkyl quaternaryammonium hydroxide and a benzyl-tri-lower alkyl quaternary ammoniumhydroxide, and

(c) neutralizing the reaction mixture with an acid selected from thegroup consisting of a hydrohalic acid, sulfuric acid, phosphoric acid, alower alkane sulfonic acid, a benzene sulfonic acid, a lower alkanecarboxylic acid and a halogenated-lower alkane carboxylic acid.

2. Process as claimed in claim 1, wherein a methyl 2-picolinium halideis used as the lower alkyl 2-picolinium salt starting material.

3. Process as claimed in claim 2, wherein 2-picolinium methochloride isused as the methyl 2-picolinium halide.

4. Process as claimed in claim 1, wherein a liquid lower alkyl nitriteis used as the alkyl nitrite reactant.

5. Process as claimed in claim 4, wherein a member selected from thegroup consisting of isopropyl, n-butyl and isoamyl nitrite is used asthe liquid alkyl nitrite.

6. Process as claimed in claim 1, wherein an alkali metal hydroxide isused as the base.

7. Process as claimed in Claim 6, wherein a member selected from thegroup consisting of sodium and potassium hydroxide is used as the alkalimetal hydroxide.

8. Process as claimed in claim 1, wherein a hydrohalic acid is used asthe acid.

.9. Process as claimed in claim 8, wherein hydrochloric acid is used asthe hydrohalic acid.

10. Process for the preparation of methyl 2-pyridiniurnaldoxime halideswhich comprises (a) mixing a methyl 2-picolinium halide with a liquidalkyl nitrite containing 3 to 5 carbon atoms in about a molar ratio,

(b) adding to the reaction mixture an equivalent amount of an alkalimetal hydroxide at a temperature not exceeding room temperature and (c)neutralizing the reaction mixture with a hydrohalic acid.

11. Process as claimed in claim 10, wherein methyl 2-picolinium chlorideis used as the methyl 2-picolinium halide.

12. Process as claimed in claim 10, wherein a member selected from thegroup consisting of isopropyl, n-butyl and isoamyl nitrite is used asthe liquid alkyl nitrite.

13. Process as claimed in claim 10, wherein sodium hydroxide is used.

14. Process as claimed in claim 10, wherein hydrochloric acid is used asthe hydrohalic acid.

15. Process as claimed in claim 1, wherein the reaction is carried outbetween -10 and +10 C.

16. Process as claimed in claim 1, wherein the aliphatic nitrite and thebase are added simultaneously.

References Cited UNITED STATES PATENTS 2,816,113 12/1957 Wilson et al.260296 3,150,135 9/1964 Forman 260-296 3,155,674 11/ 1964 McDowell260--296 OTHER REFERENCES Kirk-Othimer Encyclopedia of ChemicalTechnology, vol. 9 (1952) Interscience, pp. 696-7.

JOHN D. RANDOLPH, Primary Examiner.

WALTER A. MODANCE, Examiner.

A. L. ROTMAN, Assistant Examiner.

